This proposal outlines a five-year career development program designed to prepare Dr. Koff for a career as an academic physician-scientist in pulmonary medicine. Dr. Koff is interested to study airway epithelial innate immune responses to respiratory viruses. This interest arose from knowledge that Rhinovirus (RV) infections are responsible for exacerbations of chronic airway diseases. To date, no effective therapy for these exacerbations exists, so investigating novel viral mechanisms will be important for effective antiviral therapy. Dr. Koff has been examining airway epithelial innate immune responses to pathogens such as RV, and he has focused on a pro-inflammatory cascade that activates an epithelial surface receptor [epidermal growth factor receptor (EGFR)] to recruit neutrophils via the production of IL-8/CXCL8, and an anti-viral cascade that produces IP-10/CXCL10 to recruit natural killer (NK) cells, specialized lymphocytes that target and kill virus-infected cells. Dr. Koff proposes to test the hypotheses that: (1) RV initiates both EGFR and IP-10 pathways in airway epithelium, which have a common origin but divergent downstream signals;(2) these pathways are reciprocal, and the balance between the two determines certain cell outcomes;and (3) NK cells, recruited by IP-10, target and kill RV-infected airway epithelium. Well established techniques that include ELISA, flow cytometry, RT-PCR, immunoblot, and siRNA will be used. Dr. Koff's mentor, Dr. Jay Nadel, and co-mentor, Dr. Lewis Lanier, are productive and well-funded scientists with expertise in airway epithelial cell biology and NK cell immunology with outstanding track records for training successful academic physicians. Dr. Koff has assembled an expert scientific advisory committee who will oversee his research and help implement an educational plan that will enrich his development. The Cardiovascular Research Institute and the University of California, San Francisco are committed to developing the academic career of Dr. Koff, and at the end of the grant period, Dr. Koff will be well equipped to embark on a career as an independent investigator focused on combining pulmonary cellular biology and immunology to understand the mechanisms of airway epithelial innate immune responses to viral infection. In addition to causing the common cold, Rhinovirus is responsible for causing exacerbations of chronic airway diseases (e.g. asthma). However, to date there are no effective therapies to treat these exacerbations. This proposal will investigate the signaling pathways of airway epithelial responses to Rhinovirus infection, and the discovery of novel mechanisms may provide targets for future therapies.